Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Definitions

• This invention relates to fast disintegrating tablets and particularly to tablets which not only disintegrate rapidly but also have good friability characteristics.
• the tablets of this invention are particularly suitable for rapidly releasing a water soluble or water insoluble drug in granular or microencapsular form, e.g where the drug is for controlled, sustained or targeted release, or where the drug requires gastric protection or taste masking, etc.
• coated multiparticulate dosage forms have become increasingly important in the development of both controlled release and taste masked pharmaceutical formulations.
• microencapsulation is widely recognised as a versatile technique for the coating of particles of active drugs to enhance their therapeutic value.
• Microencapsulation is achieved by two distinct processes, namely coacervation/phase separation and air suspension coating. These processes envelop small particles of the drug substance into minute, discrete, solid packages which to the naked eye appear as a fine powder.
• Such solid oral dosage forms are particularly advantageous for applying large single doses orally, since a tablet or other shaped form can be difficult to swallow especially for patients such as children and the elderly. These problems can be exacerbated when no water is available.
• Chewable tablets containing coated particles of active drugs are a well-known dosage form (see for instance the textbook “Pharmaceutical dosage form—tablets” Vol. 1 edited by H A Lieberman et al. Marcel Dekker, Inc. (1989).
• fast dispersing or disintegrating tablets have been developed.
• Fast disintegrating tablets containing particles of active are based on the presence of one or more disintegrating agents which allow the tablet, when taken up by mouth, to disgregate quickly into many coated cores of active.
• disintegrating agents which allow the tablet, when taken up by mouth, to disgregate quickly into many coated cores of active.
• the presence of such ingredients tends to weaken the tablet's structure leading to poor friability values.
• fast disintegrating tablets have suffered from problems due to their limited physical integrity as evidenced by their high friability compared to the conventional tablet forms.
• fast disintegrating tablets have previously been found to fracture or chip easily and therefore require careful packaging and handling prior to placing them in the mouth.
• such tablets may also contain other pharmaceutical ingredients for example swelling agents or thickening agents which are responsible for producing, when the tablets disintegrates directly in the mouth or in a glass of water, a viscous medium that facilitates the suspension of the solid particles.
• swelling agents or thickening agents which are responsible for producing, when the tablets disintegrates directly in the mouth or in a glass of water, a viscous medium that facilitates the suspension of the solid particles.
• Freeze drying processes have been used to prepare fast disintegrating dosage forms.
• the product obtained is characterised by a solid dried highly porous microstructure of the soluble supporting agent (i.e. mannitol, glycine, lactose, gelatins, etc) in which the active is homogeneously dispersed.
• the soluble supporting agent i.e. mannitol, glycine, lactose, gelatins, etc
• this technology produces a product which rapidly disintegrates in water or in the oral cavity, a drawback is represented by the poor physical integrity of its physical structure which severely limits further manufacturing operations such as forming blister packs.
• freeze drying technology in manufacturing such dosage forms is the high production costs because of the lengthy duration of each freeze drying cycle (normally from 24 to 48 hours).
• the complexity of the industrial plants is another important factor which prejudices the large scale use of this technology for the development of rapid disintegrating tablets.
• thermal shocks as a direct consequence of each freeze drying cycle, might physically modify the physical-chemical properties of the outer membrane of microencapsulated particles.
• a fast disintegrating tablet such as a tablet which disintegrates in the mouth in 75 seconds or less
• a fast disintegrating tablet having an enhanced structural integrity, for instance having a friability lower than 2.0% according to USP XXIII test; preferably lower than 1.5% and most preferably 1.0% or lower.
• a fast disintegrating tablet preferably having an extremely short disintegration time, quantifiable in less than 20 seconds, when taken directly by mouth without water and without the necessity of chewing the tablet and wherein the active is in the form of microcapsules having controlled release and/or gastro-resistance and/or taste masking properties.
• any multiparticulate fast disintegrating tablet should possess a physical integrity approaching that of a conventional tablet without limiting the disintegration performance of the tablet.
• This mixture comprises at least one water insoluble inorganic excipient and at least one disintegrant in appropriate amounts and optionally combined with one or more water soluble constituents.
• disintegration time of tablets having satisfactory mechanical properties depends not only on the quantity of disintegrant used, but also on the quantity of the insoluble inorganic excipient and if present soluble excipient and the relative weight ratio between these components (disintegrant, insoluble excipient and drug and if present soluble excipient).
• Tablets are obtained by mixing the components of the solid mixture in powdery form, (where the active is in the form of coated or uncoated particles) and directly applying compression forces to produce tablets having enhanced physical integrity without affecting their excellent disintegration properties.
• this invention provides a fast disintegrating tablet comprising a drug in multiparticulate form, e.g. granular or microencapsulated; one or more water insoluble inorganic excipients, one or more disintegrants; and optionally one or more substantially water soluble excipients, the amounts of said ingredients being such as to provide a disintegration time in the mouth in the order of 75 seconds or less, eg. 40 seconds or less, preferably less than 30 seconds, most preferably less than 20 seconds.
• Friability is an index which provides a measure of the ability of a tablet to withstand both shock and abrasion without crumbling during the handling of manufacturing, packaging, shipping and consumer use.
• a laboratory device known as Roche friabilometer As a means of controlling and quantifying the measurement of friability, a laboratory device known as Roche friabilometer, is routinely used. The method to determine such measurement refers to both USP XXIII and European Pharmacopoeia prescriptions. Conventional tablets that lose less than 0.5 to 1.0% in weight are generally considered particularly acceptable. Of course, depending on their physical characteristic, fast disintegrating tablets previously known have higher friability weight losses.
• a further aspect of this invention provides a tablet adapted to disintegrate in less than about 75 seconds , preferably 40 seconds or less comprising a drug in multiparticulate form, e.g. granular or microencapsulated; one or more water insoluble inorganic excipients; one or more disintegrants; and optionally one or more substantially water soluble excipients, the amount of said ingredients and the tensile strength of the tablet being such that the tablet has a friability value less than 2%, preferably less than 1.5% most preferably about 1% or less.
• the drug used is preferably substantially water insoluble or is coated with an outer substantially water insoluble membrane or layer which protects/isolates the active at least through the mouth and throat and if required through the stomach or through the stomach and the small intestine.
• the coated or uncoated microparticles of the drug may typically have a particle size distribution ranging from approximately 20 to about 1000 microns. Average particle size can be for example 120 to 150 microns or more, eg. 200 microns. In order to produce a palatable mouth feel without grittiness, microparticles with a maximum particle size lower than 700 microns are preferred.
• Coated microparticles of active drug can be obtained through various well known technologies such as for instance, but not limited to, phase separation and fluid bed coating. Coated microparticles having taste masking properties are preferably obtained by phase separation (coacervation) since this process ensures the most uniform coverage of a drug substance.
• Uncoated microparticles of active include substantially water insoluble particles which can be produced for instance by well known technologies such as dry granulation, wet granulation, melt granulation, direct pelletization with a rotor granulator and extrusion spheronisation.
• the amount of coated or uncoated multiparticulate drug is generally 14% or more of the tablet weight depending on the active and can be up to 75% or more. Typical ranges of coated or uncoated active are from 20% to 70% by weight of tablet. For actives such as ibuprofen, preferred ranges are from 40% to 60%.
• Disintegrating agents suitable for use in the present formulations include pharmaceutical excipients which facilitate the break-up of a tablet when it is placed in aqueous environment. Disintegrants once in contact with water, swell, hydrate, change in volume or form to produce a disruptive force that opposes the efficiency of the binder/s causing the compressed table to break apart. They belong to different morphological classes and possess different functionality properties. A non-limiting list of the different classes of disintegrants or mixtures thereof which can be used in the formulations of the present invention is given below:
• natural starches such as maize starch, potato starch etc.
• directly compressible starches such as starch 1500
• modified starches such as carboxymethylstarches and sodium starch glycolate which are available as PRIMOJEL® and EXPLOTAB® and EXPLOSOL®
• starch derivatives such as amylose.
• cross-linked polyvinylpyrrolidones e.g. crospovidones available as e.g. POLYPLASDONE XL® and KOLLIDON XL®.
• modified celluloses such as cross-linked sodium carboxymethylcelluloses available as, e.g., AC-DI-SOL®, PRIMELLOSE®, PHARMACEL XL®, EXPLOCEL®, and NYMCEL ZSX®;
• Microcrystalline cellulose e.g. AVICEL®, PHARMACEL®, EMCOCELL®, VIVAPUR®.
• Methacrylic acid-divinylbenzene copolymer salts available as eg AMBERLITE® IRP-88.
• microcrystalline cellulose is often regarded as a weak disintegrant, it is also used in preparing tablets because of its properties as a filler and plasticising agent and therefore can be regarded as a substantially water insoluble excipient.
• this invention provides a tablet as defined above which further comprises microcrystalline cellulose.
• the multiparticulate fast disintegrating tablets of this invention are obtained by standard tableting procedures such as by forming a dry mixture which comprises all of the above mentioned components prior to direct compression in punches/dies.
• Substantially water insoluble inorganic excipients include for example, water insoluble fillers and/or diluents, eg salts such as dibasic calcium phosphate, calcium phosphate tribasic, calcium sulfate and dicalcium sulfate. Particularly preferred is dibasic calcium phosphate (hydrated or anhydrous) with the anhydrous form being most preferred.
• the particle size of the water insoluble inorganic excipient is such that at least 35% of the particles are larger than 75 ⁇ m . Preferably at least 45% of the particles are larger than 75 ⁇ m. Most preferably at least 80% of the particles are larger than 75 ⁇ m.
• Substantially water soluble components that may be used in the present invention include for example, compression sugars or soluble fillers (e.g. lactose, sucrose, amylose, dextrose, mannitol, inositol etc.), flavouring agents, sweeteners (e.g. aspartame, saccharine etc.), pH adjusting agents (e.g. fumaric acid, citric acid, sodium acetate etc.), binders (e.g. polyethylene glycols, soluble hydroxyalkylcelluloses, polyvinylpyrrolidone, gelatins, natural gums-etc.), surfactants (e.g. sorbitan esters, docusate sodium, sodium lauryl sulphate, cetriride etc.), soluble inorganic salts (eg sodium carbonate, sodium bicarbonate, sodium chloride etc.).
• compression sugars or soluble fillers e.g. lactose, sucrose, amylose, dextrose,
• the dry mixture of the essential components of the invention gives rise upon direct compression to fast disintegrating tablets having a disintegration time of less than 20 seconds in the oral cavity.
• the insoluble inorganic salt used as filler/diluent eg di- or tri-basic calcium phosphate
• organic filler eg microcyrstalline cellulose
• water insoluble lubricant eg magnesium stearate, sodium stearyl fumarate, stearic acid or glyceryl behenate
• glidant eg talc, silicon dioxide etc.
• substantially soluble components eg the amount of compression sugars (eg lactose, flavouring agents, sweeteners (aspartame), binders (eg PVP) and surfactants etc.
• compression sugars eg lactose, flavouring agents, sweeteners (aspartame), binders (eg PVP) and surfactants etc.
• (C) disintegrant especially super-disintegrant such as maize starch or modified starches, cross-linked polyvinyl pyrrolidone or sodium carboxymethylcellulose.
• the amount of disintegrant should not be excessive and is therefore preferably in the range 0.5 to 30%, most preferably 1-20%, most preferably 2-15% by weight of the tablet.
• the amount of the substantially water insoluble components (A) can be for example in the range 50-99.5% of the formulation by weight, eg. 60-99.5%, preferably 70-95%, most preferably about 72-92% by weight.
• the amount of substantially water insoluble inorganic excipient may be for example in the range 2-40% of the formulation by weight, eg 2-35%, preferably 4-25%, most preferably about 6-18% by weight.
• disintegration time is optimised by compensating for the absence of insoluble drug or insoluble microencapsulated drug (where the drug can be soluble or insoluble) by including an insoluble filler, eg microcrystalline cellulose, silicon dioxide or by increasing the amount of insoluble inorganic excipient, eg calcium salt such as dibasic calcium phosphate.
• the amount of coated or uncoated active relative to substantially water insoluble inorganic excipient is in the range 25:1 to 0.35:1; preferably 10:1 to 0.37:1; most preferably about 9:1 to 2:1.
• the amount of the optional substantially water soluble component(s) (B) is for example in the range 0-25% of the formulation by weight, preferably 0-20%, most preferably about 4-16% by weight.
• Microcrystalline cellulose can be present in the range up to 40% by weight of the formulation, preferably 5-30%, most preferably about 8 to 25%, eg 12-22%.
• the amount of water insoluble inorganic excipient(s) relative to super disintegrant(s) can be in the range between 1:9 and 9:1; preferably in the range 1:5 to 4:1 by weight; most preferably in the range 1:2.5 to 3.6:1 by weight.
• the ratio of water-insoluble inorganic excipient to microcrystalline cellulose is preferably in the range 100:1 to 1:9 by weight.
• the powder formulations of this invention are conveniently prepared using conventional procedures to ensure homogeneous mixing of the components. Tablets may be formed from such formulations by direct compression methods.
• Powder mixtures were prepared according to the general procedure given below:
• the excipients (except magnesium stearate) were premixed in a polyethylene bag by manual shaking and sieved through a 700 ⁇ m screen. Microcapsules were added to the excipient mixture and mixed in a 8 liter or 1.6 liter cube using an Erweka AR400 blender (D-Heusenstamm) for 20 minutes at 20 rpm. Magnesium stearate if used was added to mixture at this stage and mixed for 5 minutes at 20 rpm. Compression was performed with a rotary tableting machine (Ronchi mod. AM13/8, I-Cinisello Balsamo), equipped with either two 12 mm or 15 mm diameter scored flat punches. Operating conditions were standardised at 20 rpm. The tableting machine was instrumented to measure compression and ejection forces with strain gauges, interfaced to a Yokogawa mod. 3655E data computer and analyser.
• Hardness was measured by diametral crushing on a Schleuninger mod. 6D hardness tester (CH-Solothurn). The tests were performed according to European Pharmacopoeia 1997 Section 2.9.8.
• Average tablet weight and weight variation were calculated using a Mettler mod. PM460 balance (Sae Scientifica, I-Mazzo di Rho), equipped with calculator Stat Pac-M and printer GA44.
• Thickness was determined using a Mitutoyo mod. 500-311 caliper (Tecnogalencia, I-Cernusco sul Naviglio).
• Friability was measured by an Erweka TA friabilometer (D-Heusenstamm). The test was performed for 4 minutes using 20 tablets.
• Disintegration time was determined by placing a tablet into a 2 liter beaker (14 cm diameter, 18 cm height) containing 1 liter of water at room temperature whilst continuously stirring using a helix at 100 ⁇ 5 rpm. The helix was placed in a fixed position just below the water surface. The completes dispersion of the tablets was considered as the end point.
• Tablets having 15 mm diameter were made from the ingredients of Example 1 with tensile strengths of 0.38 N/mm 2 (compression force 20 kN) and 0.47 N/mm 2 (compression force 25.2 kN). Disintegration times were 20 ⁇ 1 seconds and 21 ⁇ 1 seconds respectively.
• Tablets (15 mm diameter) were also made according to
• Example 1A (based on Example 1 of U.S. Pat. No. 5,464,632) which differed by containing no inorganic insoluble filler/diluent. At tensile strengths of 0.39 and 0.59 N/mm 2 the latter produced much slower disintegration times of 40 ⁇ 2 seconds and 46 ⁇ 2 seconds respectively.
• Friability values for the 15 mm diameter tablets of Example 1 were improved by compression being 4.4% (compression force 20 kN) and 1.4% (compression force 25.2 kN) for the respective formulations above.
• Formulations having the following ingredients shown in TABLE 3 below were prepared and made into 12 mm diameter tablets.
• Tablets (12 mm diameter) prepared according to the formulation of Example 3A having a tensile strength of 0.67 N/mm 2 showed complete disintegration only after 103 ⁇ 5 seconds.
• Friabilities of both tablets of Examples 3 and 3A were both very good at ⁇ 0.5% but in view of the slow disintegration of the Example 3A formulation this cannot be considered to constitute a rapidly disintegrating tablet.
• a formulation was made up according to the ingredients in TABLE 4 below. Tablets were prepared having 12 mm diameter.
• Disintegration times were found to fall below about 20 seconds at tensile strength values ⁇ 0.7 N/mm 2 .
• the friability value at tensile strength 0.68 was found to be 0.2% and the in vitro disintegation time was 18 seconds
• Example 3 shows that the presence of microcrystalline cellulose (Avicel PH101) in the ratio 75:45 to dibasic calcium phosphate gives a faster disintegration time than tablets containing no microcrystalline cellulose (Example 3) and also improves friability values.
• Ibuprofen microcapsules 2400 g cellulose acetate phthalate membrane
• Compression was performed with a rotary tableting machine (Ronchi mod. AM 13/8), equipped with two 12 mm diameter scored flat punches. Operating conditions were standardised at 20 rpm and with respect to obtaining tablets with tensile strengths of about 0.45 to 0.55 N/mm 2 .
• Each tablet contains 240 mg of ibuprofen microcapsules corresponding to 200 mg of active.
• Compression was performed with a rotary tableting machine (Ronchi mod. AM13/8), equipped with two 9 mm diameter scored flat punches. Operating conditions were standardised at 20 rpm and with respect to obtaining tablets with a tensile strength by using compression forces of about 4.5 kN. Each tablet having a weight of 261 mg contains 62 mg of fluoxetine microcapsules corresponding to 20 mg of active. The friability was 0.5% and the in vitro disintegration time was 17 seconds.
• Cimetidine microcapsules 2400 g ethylcellulose membrane
• Strawberry flavour 190 g iii
• Magnesium stearate 140 g iv) Crospovidone 250 g Maize starch 60 g
• Compression was performed with a rotary tableting machine (Ronchi mod. AM 13/8), equipped with two 12 mm diameter scored flat punches. Operating conditions were standardised at 20 rpm using compression forces of 17-20 kN to obtain tablets with a tensile strength of about 0.60 N/mm 2 . Each tablet had a weight of 470 mg and contained 240 mg of cimetidine microcapsules corresponding to 200 mg of active. The friability value was 0.6% and the in vitro disintegration time was 22 seconds.
• Examples 8 and 9 illustrate the use of a mixture of super-disintegrants.
• Powder mixture were prepared according to the general procedure given below:
• In vitro disintegration time was determined by placing a tablet into a 2 liter beaker 14 cm diameter, 18 cm height containing 1 liter of water at room temperature whilst continuously stirring using a helix at 100 ⁇ 5 rpm. The helix was placed in a fixed position just below the water surface. The complete dispersion of the tablets was considered as the end point.
• Ibuprofen microcapsules 247 active 200 (cellulose acetate phthalate membrane) Maize starch 65 Sodium croscarmellose (Ac-Di-Sol ®) 20 # Citric acid 15 Saccharin 15 Strawberry flavour 16 Microcrystalline cellulose (Avicel PH112) 55 Dibasic calcium phosphate (Dicafos C52-22) 34 Silicon dioxide 10 Talc ⁇ 75 ⁇ m 20 Magnesium stearate 13 TABLET WEIGHT 510 mg
• Ibuprofen microcapsules 247 active 200 (cellulose acetate phthalate membrane) Maize starch 65 Citric acid 10 Saccharin 24 Banana flavour 12 Microcrystalline cellulose (Avicel PH112) 68 Dibasic calcium phosphate (Dicafos C52-22) 41 Silicon dioxide 10 Talc ⁇ 75 ⁇ m 20 Magnesium stearate 13 TABLET WEIGHT 510 mg
• Ibuprofen microcapsules 247 active 200 (cellulose acetate phthalate membrane) Sodium croscarmellose (AcDiSol ®) 20 Citric acid 10 Saccharin 24 Banana Flavour 12 Microcrystalline cellulose (Avicel PH112) 98 Dibasic calcium phosphate (Dicafos C52-22) 56 Silicon dioxide 10 Talc ⁇ 75 ⁇ m 20 Magnesium stearate 13 TABLET WEIGHT 510 mg
• Ibuprofen microcapsules 247 active 200
• Amberlite ® IRP 88 55 Citric acid 15 Saccharin 15 Strawberyy Flavour 16
• Microcrystalline cellulose Avicel PH112
• Dibasic calcium phosphate Dibasic calcium phosphate (Dicafos C52-22)
• Silicon dioxide 10
• Talc ⁇ 75 ⁇ m 20
• Ibuprofen microcapsules 247 active 200
• Alginic acid Protacid ® F-120
• Citric acid Saccharin
• Strawberry flavour 16
• Microcrystalline cellulose Avicel PH112
• Dibasic calcium phosphate Dibasic calcium phosphate (Dicafos C52-22)
• Silicon dioxide 10
• Talc ⁇ 75 ⁇ m 20
• Ibuprofen microcapsules 240 active 200 (cellulose acetate phthalate membrane) Maize starch 60 Sodium croscarmellose (AcDiSol ®) 16 Sodium starch glycolate (Explotab ®) 15 Citric acid 15 Saccharin 15 Mint-Liquorice flavour 16 Microcrystalline cellulose (Avicel PH112) 57 Dibasic calcium phosphate (Dicafos C52-22) 35 Silicon dioxide 15 Talc ⁇ 75 m 25 Magnesium stearate 11 TABLET WEIGHT 520 mg
• Tablets were made using two 9 mm diameter flat punches.

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• 1999
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